Use of Donor Derived Cell Free DNA for Long Term Rejection Surveillance in OHT Recipients

Abstract

IntroductionThe advent of donor-derived cell free DNA (dd cf DNA) testing has transformed care for orthotopic heart transplant (OHT) recipients by reducing the number of invasive endomyocardial biopsies (EMB) for surveillance of acute rejection (AR). The dd cf DNA is elevated in any form of graft injury ranging from AR to ischemic injury from cardiac allograft vasculopathy (CAV). When used in combination with gene expression profiling, the AUC for the combination to rule out acute rejection is about 80.1% However, all the data about using dd cf DNA for AR surveillance is from studies done in the first few years after OHT. There is no data or recommendation on using dd cf DNA in long-term OHT survivors (>5 years). Here we present an interesting case of acute rejection detected by dd cf DNA in a patient who is 8 years post OHT.Case Report55 yo African American male with a history of OHT for non ischemic cardiomyopathy in 2013. He had no previous history of AR or CAV. As part of his routine post-transplant annual work-up, dd cf DNA was checked and it came back elevated at 0.95 % (Ref: >0.25% - significantly elevated, >1% - high probability of AR). Donor specific antibodies were negative. Echocardiogram revealed an ejection fraction of 55-60%. He had a right heart catheterization, which showed normal to low filling pressures and preserved cardiac index. EMB revealed Grade 1R cellular rejection as well as swollen endothelial cells, and >50% capillary positive staining with C4d consistent with acute antibody-mediated rejection (pAMR2). He was successfully treated with plasmapheresis/IVIG x 5 cycles and Rituximab. On further probing, the patient admitted to missing a few doses of his immunosuppression (IS) medications.SummaryThis case highlights the successful use of dd cf DNA for allograft rejection surveillance several years (>5 years) after OHT. However, there is sparse data in this population. Further studies are needed in large patient groups to assess the validity and reproducibility of dd cf DNA in long-term surveillance of rejection. The advent of donor-derived cell free DNA (dd cf DNA) testing has transformed care for orthotopic heart transplant (OHT) recipients by reducing the number of invasive endomyocardial biopsies (EMB) for surveillance of acute rejection (AR). The dd cf DNA is elevated in any form of graft injury ranging from AR to ischemic injury from cardiac allograft vasculopathy (CAV). When used in combination with gene expression profiling, the AUC for the combination to rule out acute rejection is about 80.1% However, all the data about using dd cf DNA for AR surveillance is from studies done in the first few years after OHT. There is no data or recommendation on using dd cf DNA in long-term OHT survivors (>5 years). Here we present an interesting case of acute rejection detected by dd cf DNA in a patient who is 8 years post OHT. 55 yo African American male with a history of OHT for non ischemic cardiomyopathy in 2013. He had no previous history of AR or CAV. As part of his routine post-transplant annual work-up, dd cf DNA was checked and it came back elevated at 0.95 % (Ref: >0.25% - significantly elevated, >1% - high probability of AR). Donor specific antibodies were negative. Echocardiogram revealed an ejection fraction of 55-60%. He had a right heart catheterization, which showed normal to low filling pressures and preserved cardiac index. EMB revealed Grade 1R cellular rejection as well as swollen endothelial cells, and >50% capillary positive staining with C4d consistent with acute antibody-mediated rejection (pAMR2). He was successfully treated with plasmapheresis/IVIG x 5 cycles and Rituximab. On further probing, the patient admitted to missing a few doses of his immunosuppression (IS) medications. This case highlights the successful use of dd cf DNA for allograft rejection surveillance several years (>5 years) after OHT. However, there is sparse data in this population. Further studies are needed in large patient groups to assess the validity and reproducibility of dd cf DNA in long-term surveillance of rejection.